Understanding how neuronal nicotinic acetylcholine (nAChRs) regulate central nervous system (CNS) function will depend on the identification of particular roles for specific receptor subunits. Existing data indicate that certain subtypes of nicotinic receptors contribute to different behavioral effects of nicotine. For example, the effect of nicotine on exploratory activity appears to be regulated by receptor subtypes that bind nicotine with high affinity, while the effects of nicotine on sensorimotor gating and nicotine induced-seizures are regulated by receptors that bind alpha-bungarotoxin. Similar relationships exist between the development of tolerance to nicotine and increases in the different nicotinic receptor subtypes. This project will test the hypothesis that the different nicotinic receptor subunits regulate the sensitivity to nicotine and the development of nicotine tolerance. The firs aim of the project will examine the role of individual nAChR subunits in regulating normal baseline behavioral responses. N Nicotine affects numerous behavioral responses in mice and rats including activity, motor coordination, anxiety, sensorimotor gating, and analgesic-related responses. The second aim will evaluate the effects of nicotine on a wide array of behavioral assays to determine if different nicotinic receptors regulate different behavioral effects of nicotine. For these studies dose response curves will be generated for the effects of nicotine in alpha7-, alpha5-, alpha4-, beta2-, or beta4-deficient mice on open-field activity, several assays of anxiety, rotarod performance, prepulse inhibition, and the hot-plate test. Nicotine also improves learning and memory performance. our third aim of this project will determine if the alpha7 or beta2 subunits, which are known to be expressed in the hippocampus, regulate the effects of nicotine on hippocampal-dependent learning and memory performance. The final aim will investigate the role of alpha7 and beta2 subunits in the development of nicotine tolerance to several behavioral effects of nicotine following chronic nicotine infusions. The findings from these studies will provide insight into the functional role of different nAChR subunits in nicotine addiction and dependence.